FDA Panel Loosens Noose on Avandia

by David Pittman,Washington Correspondent, MedPage Today
June 6, 2013

MedpageToday

SILVER SPRING, Md. -- A panel of FDA advisers thinks it is time to ease restrictions on access to Avandia (rosiglitazone), a onetime multimillion dollar blockbuster drug brought low by reports that it increased the risk of heart attacks.

In a combined meeting of separate FDA advisory committees, 20 of 26 panelists voted Thursday to recommend removing or modifying rosiglitazone's highly restrictive label and distribution system. Five voted to keep the product's risk evaluation and mitigation strategy (REMS) as it is now. One panelist voted to remove the product from the market.

Of the 20 panelists who voted to remove or modify the labeling and distribution system, 13 voted to modify it and seven voted to remove the REMS entirely.

The vote of the FDA's Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees comes 3 years after the agency placed severe restrictions on the drug following concerns of increased risk of cardiovascular events.

The FDA in its 2010 decision required a re-examination of manufacturer GlaxoSmithKline's (GSK) RECORD trial -- the only large, randomized outcomes trial of rosiglitazone. The trial's method and results were questioned, and re-adjudication results were presented before the panel this week.

Duke Clinical Research Institute (DCRI), the independent reviewer GSK selected for the re-adjudication, found the hazard ratio for cardiovascular death, myocardial infarction (MI), and stroke to be 0.95 (95% CI 0.78-1.17), which is roughly the same as the result of 0.93 (95% CI, 0.74-1.15) from the original study. It was also mostly unchanged from 2010 when breaking down each category individually.

While stroke outcomes were better under rosiglitazone, MI was worse when compared to pioglitazone (Actos).

But the results reaffirming GSK's original findings "moved the needle," as some noted, and helped reassure Thursday's panelists that the drug was no more unsafe than other diabetes products in its class.

"I find no substantial evidence or information that rosiglitazone is unsafe," Arthur Moss, MD, cardiology professor at the University of Rochester School of Medicine in New York, said, adding its ability to lower blood sugar without causing hypoglycemia proves it could be of use.

Sanjay Kaul, MD, director of cardiovascular fellowship training at Cedars-Sinai Medical Center in Los Angeles, said there's not enough evidence to support or blame rosiglitazone's safety and therefore physicians should be able to choose it if they desire.

At the 2010 advisory committee meeting, panelists raised questions about the reliability of the trial's data, its collection, and interpretation. "I no longer have those concerns," said Marvin Konstam, MD, chief physician executive of the Cardiovascular Center at the Tufts Medical Center in Boston.

Other panelists expressed concern with the trial's design. It was open-label and unblinded, opening up the possibility of bias.

Many panelists called for an additional randomized, controlled trial to answer once and for all questions about rosiglitazone's cardiovascular safety. However, such a trial would be difficult given the great amount of publicity rosiglitazone has gained in recent years, they said.

"It may well not be feasible to conduct a trial that answers the questions we have," Susan Heckbert, MD, PhD, epidemiology professor at the University of Washington in Seattle, said.

Moss called for a phase IV study of the 3,400 patients currently taking the drug.

The decision is now in the hands of the FDA. But the FDA has no regulatory deadline by which to make a decision, and it's unclear when the agency will make a ruling, an FDA spokeswoman said.

The FDA isn't obligated to follow the advice of its advisory committees but usually does.

Rosiglitazone-containing products carry the most restrictive type of REMS, that which includes a MedGuide and elements to assure safe use.

Only physicians who hold special certification and certain pharmacies are able to prescribe and dispense the drug. Also, rosiglitazone is limited to patients who are unable to achieve glycemic control on other medications and who are accepting of increased myocardial risks.

Because of the restrictions on prescribing, the number of patients taking the drug has fallen from more than 117,000 at its peak to 3,400 today. Drug regulators in Europe banned the drug altogether because of safety concerns.

The FDA might have options to soften the REMS. For example, the agency could remove certification requirements for pharmacies and prescribers, said Elaine Morrato, DrPH, professor of health systems management and policy at the University of Colorado in Aurora.

At the 2010 FDA panel, 12 of 33 members voted to recommend withdrawing the product from the market completely. Another 10 voted that rosiglitazone should remain available but with added restrictions and a revised label to increase warnings.

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